This invention relates to a novel epoxysuccinamide derivative and remedies for treating bone diseases and arthritis using the same.
In the bone tissue, bone resorption and bone formation are continuously and simultaneously performed by osteoclasts and osteoblasts, respectively. The structure and amount of the bone is kept on their balance. However, if the excessive bone resorption continues for a long time, bone diseases such as osteoporosis develop. In addition, malignant hypercalcemia and Paget""s disease are accompanied by abnormal enhancement of excessive bone resorption.
The process of bone resorption by osteoclasts can be divided into two steps, namely, dissolution of minerals (i.e., decalcification) and degradation of bone matrix. The degradation of bone matricx is considered to occur by the action of lysosomal enzymes According to recent studies, it is recognized that among the lysosomal enzymes, cathepsin L and its analogous enzyme, namely, cathepsin K, which are cysteine proteases, play a key role [Kakegawa and Katsunuma, Molecular Medicine, 30(10), 1310-1318 (1993), Tezuka et al., J. Biol. Chem., 269, 1106-1109(1994), Inui et al., J. Biol. Chem., 272, 8109(1997)]. Further, it has been reported that a cysteine protease inhibitor blocks the bone resorption [J. M. Delaisse et al., Biochem. Biophys., Res. Commun., 125, 441-447(1984)]. Therefore, compounds which inhibit action of cysteine protease such as cathepsin L are considered to be of value for treating bone diseases such as osteoporosis.
Japanese Patent Publication No. 61-55509 describes epoxysuccinic acid derivatives (i.e., epoxysuccinamic acid compounds) as compounds for inhibiting the action of a protease which have a thiol group participating in their action.
Further, it has been already proposed that certain epoxysuccinic acid derivatives be employed for treating bone diseases [Japanese Patent Provisional Publications No. 63-284127 and No. H2-2186101].
Each of Japanese Patent Provisional Publications No. H8-41043 and H8-104684 describes that epoxysuccinamide derivatives having a specific chemical structure are effective for treating bone diseases.
WO 96/30354 describes the use of new epoxysuccinamides as remedies for treating bone diseases.
It is an object of the present invention to provide a compound and a pharmaceutical composition which are useful for prevention and treatment of bone diseases such as osteoporosis, malignant hypercalcemia and Paget""s disease.
It is another object of the invention to provide a compound and a pharmaceutical composition which are useful for treating osteoarthritis and rheumatoid arthritis which are accompanied by abnormal enhancement of activities of cysteine proteases such as cathepsin B and cathepsin L.
It is a further object of the invention to provide a compound which is useful as a medicine for treating diseases in which cathepsin B and cathepsin L participate, such as muscular dystrophy and muscular atrophy.
The present inventors have earnestly studied to accomplish the abovementioned objects and have found that new epoxysuccinamide derivatives having the below-mentioned formula (1) or their physiologically acceptable salts show a potent inhibitory action against cathepsin L and cathepsin L, and further show high effectiveness in inhibiting bone resorption and in treating a postmenopausal osteoporosis model, and furthermore show effectiveness in treating a rheumatoid arthritis model: salt: 
wherein
R1 represents a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, an alkenyl group having 2 to 10 carbon atoms, an alkynyl group having 2 to 10 carbon atoms, an aryl group having 6 to 20 carbon atoms, an aralkyl group comprising an aryl group having 6 to 20 carbon atoms and an alkyl group having 1 to 6 carbon atoms, a heterocyclic group having 3 to 12 carbon atoms, or a heterocyclic-alkyl group comprising a heterocyclic group having 3 to 12 carbon atoms and an alkyl group having 1 to 6 carbon atoms;
R2 represents an alkyl group having 1 to 10 carbon atoms, an alkenyl group having 2 to 10 carbon atoms, an alkynyl group having 2 to 10 carbon atoms, an aryl group having 6 to 20 carbon atoms, an aralkyl group comprising an aryl group having 6 to 20 carbon atoms and an alkyl group having 1 to 6 carbon atoms, a heterocyclic group having 3 to 12 carbon atoms, or a heterocyclic-alkyl group comprising a heterocyclic group having 3 to 12 carbon atoms and an alkyl group having 1 to 6 carbon atoms;
R3 represents a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, an alkenyl group having 2 to 10 carbon atoms, an alkynyl group having 2 to 10 carbon atoms, an aryl group having 6 to 20 carbon atoms, an aralkyl group comprising an aryl group having 6 to 20 carbon atoms and an alkyl group having 1 to 6 carbon atoms, a heterocyclic group having 3 to 12 carbon atoms, or a heterocyclic-alkyl group comprising a heterocyclic group having 3 to 12 carbon atoms and an alkyl group having 1 to 6 carbon atoms;
X represents xe2x80x94Oxe2x80x94 or xe2x80x94NR4xe2x80x94 in which R4 is a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, an aryl group having 6 to 20 carbon atoms, an aralkyl group comprising an aryl group having 6 to 20 carbon atoms and an alkyl group having 1 to 6 carbon atoms, a heterocyclic group having 3 to 12 carbon atoms, or a heterocyclic-alkyl group comprising a heterocyclic group having 3 to 12 carbon atoms and an alkyl group having 1 to 6 carbon atoms;
Y1 represents OR5 in which R5 is a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, an aryl group having 6 to 20 carbon atoms, an aralkyl group comprising an aryl group having 6 to 20 carbon atoms and an alkyl group having 1 to 6 carbon atoms, an acyl group having 2 to 20 carbon atoms, a heterocyclic group having 3 to 12 carbon atoms, or a heterocyclic-alkyl group comprising a heterocyclic group having 3 to 12 carbon atoms and an alkyl group having 1 to 6 carbon atoms, SR6 in which R6 is a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, an aryl group having 6 to 20 carbon atoms, an aralkyl group comprising an aryl group having 6 to 20 carbon atoms and an alkyl group having 1 to 6 carbon atoms, an acyl group having 2 to 20 carbon atoms, a heterocyclic group having 3 to 12 carbon atoms, or a heterocyclic-alkyl group comprising a heterocyclic group having 3 to 12 carbon atoms and an alkyl group having 1 to 6 carbon atoms, or NR7R8 in which R7 is a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, an aryl group having 6 to 20 carbon atoms, an aralkyl group comprising an aryl group having 6 to 20 carbon atoms and an alkyl group having 1 to 6 carbon atoms, an acyl group having 2 to 20 carbon atoms, a heterocyclic group having 3 to 12 carbon atoms, a heterocyclic-alkyl group comprising a heterocyclic group having 3 to 12 carbon atoms and an alkyl group having 1 to 6 carbon atoms, and R8 is a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, an aryl group having 6 to 20 carbon atoms, an aralkyl group comprising an aryl group having 6 to 20 carbon atoms and an alkyl group having 1 to 6 carbon atoms, a heterocyclic group having 3 to 12 carbon atoms, or a heterocyclic-alkyl group comprising a heterocyclic group having 3 to 12 carbon atoms and an alkyl group having 1 to 6 carbon atoms;
Y2 represents a hydrogen atom or an alkyl group having 1 to 10 carbon atoms; or
Y1 and Y2 in combination with each other can form xe2x95x90O, xe2x95x90S, xe2x95x90Nxe2x80x94R9 in which R9 is a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, an aryl group having 6 to 20 carbon atoms, an aralkyl group comprising an aryl group having 6 to 20 carbon atoms and an alkyl group having 1 to 6 carbon atoms, a heterocyclic group having 3 to 12 carbon atoms, or a heterocyclic-alkyl group comprising a heterocyclic group having 3 to 12 carbon atoms and an alkyl group having 1 to 6 carbon atoms, or xe2x95x90Nxe2x80x94OR10 in which R10 is a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, an aryl group having 6 to 20 carbon atoms, an aralkyl group comprising an aryl group having 6 to 20 carbon atoms and an alkyl group having 1 to 6 carbon atoms, a heterocyclic group having 3 to 12 carbon atoms, or a heterocyclic-alkyl group comprising a heterocyclic group having 3 to 12 carbon atoms and an alkyl group having 1 to 6 carbon atoms, provided that each of the alkyl groups for R5 to R10 can have one or more substituents selected from the group consisting of hydroxyl, amino, alkylamino having 1-6 carbon atoms, dialkylamino having 2-12 carbon atoms in total, alkoxy having 1-6 carbon atoms, carboxyl, alkoxycarbonyl having 2-7 carbon atoms, carbamoyl, alkylaminocarbonyl having 2-7 carbon atoms, dialkylaminocarbonyl having 3-13 carbon atoms in total, and guanidino; and each of the aryl groups and the heterocyclic groups for R1 to R10 may have one or more substituents selected from the group consisting of alkyl having 1-6 carbon atoms, hydroxyl, amino, alkylamino having 1-6 carbon atoms, dialkylamino having 2-12 carbon atoms in total, alkoxy having 1-6 carbon atoms, halogen, haloalkyl having 1-6 carbon atoms, cyano, nitro, carboxyl, alkoxycarbonyl having 2-7 carbon atoms, carbamoyl, alkylaminocarbonyl having 2-7 carbon atoms, dialkylamino-carbonyl having 3-13 carbon atoms in total, amidino, and guanidino.
Accordingly, the new epoxysuccinamide derivatives of the above-mentioned formula (1) or their physiologically acceptable salts are effective for preventing or treating bone diseases and arthritis.
The preferred embodiments of the invention are described below.
1) R1 of the formula (1) is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms
2) R2 of the formula (1) is an alkyl group having 1 to 6 carbon atoms, phenyl, or benzyl.
3) R3 of the formula (1) is a hydrogen atom or an aryl group having 6 to 20 carbon atoms.
4) X of the formula (1) is xe2x80x94Oxe2x80x94
5) Y1 of the formula (1) is hydroxyl, an alkoxy group having 1 to 6 carbon atoms, acetoxy, or an aralkyloxy group comprising an aryl group having 6 to 20 carbon atoms and an alkyl group having 1 to 6 carbon atoms
6) R2 of the formula (1) is isobutyl or isopropyl, R3 is a hydrogen atom, Y1 is OR5 whose R5 has the meaning defined above, and Y2 is a hydrogen atom
7) R2 of the formula (1) is isobutyl or isopropyl, R3 is an aryl group having 6 to 20 carbon atoms, Y1 is OR5 whose R5 has the meaning defined above, and Y2 is a hydrogen atom.
8) Y1 and Y2 of the formula (1) in combination with each other form xe2x95x90O.
9) The physiologically acceptable salt is an alkali metal salt.
10) A pharmaceutical composition for treating bone diseases which comprises, as an active component, an epoxysuccinamide derivative of the formula (1) or its physiologically acceptable salt.
11) A pharmaceutical composition for treating arthritis which comprises, as an active component, an epoxysuccinamide derivative of the formula (1) or its physiologically acceptable salt.
The epoxysuccinamide derivatives of the formula (1) according the present invention are further described below.
In the formula (1) R1 is a hydrogen atom, an alkyl group having 1 to 10 carbon atoms (preferably an alkyl group having 1 to 6 carbon atom, optionally a linear, branched, or cyclic alkyl group, e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, and cyclohexyl), an alkenyl group having 2-to 10 carbon atoms (preferably an alkenyl group having 2 to 6 carbon atoms, optionally a linear, branched, or cyclic alkenyl group, e.g., vinyl, 2-methyl-1-propenyl, and 2-cyclohexenyl), an alkynyl group having 2 to 10 carbon atoms (preferably an alkynyl group having 2 to 6 carbon atoms, optionally a linear or branched alkynyl group, e.g., 2-propynyl and 3-butynyl), an aryl group having 6 to 20 carbon atoms (e.g., phenyl and naphthyl), an aralkyl group comprising an aryl group having 6 to 20 carbon atoms and an alkyl group having 1 to 6 carbon atoms (e.g., benzyl, phenethyl and 3-phenyl-propyl), a heterocyclic group having 3 to 12 carbon atoms (e.g., pyridyl, pyrrolidinyl, piperidinyl, furyl, and thienyl), or a heterocyclic-alkyl group comprising a heterocyclic group having 3 to 12 carbon atoms and an alkyl group having 1 to 6 carbon atoms (e.g., furfuryl, 2-thenyl, and 2-(3-pyridyl)ethyl).
R2 is an alkyl group having 1 to 10 carbon atoms (preferably an alkyl group having 1 to 6 carbon atoms, optionally a linear, branched, or cyclic alkyl group, e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, pentyl, isopentyl, hexyl, and cyclo-hexyl), an alkenyl group having 2 to 10 carbon atoms (preferably an alkenyl group having 2 to 6 carbon atoms, optionally a linear, a branched, or a cyclic alkenyl group, e.g., vinyl, 2-methyl-1-propenyl, and 2-cyclo-hexenyl), an alkynyl group having 2 to 10 carbon atoms (preferably an alkenyl group having 2 to 6 carbon atoms, optionally a linear or branched alkynyl group, e.g., 2-propynyl and 3-butynyl), an aryl group having 6 to 20 carbon atoms (e.g., phenyl and naphthyl), an aralkyl group comprising an aryl group having 6 to 20 carbon atoms and an alkyl group having 1 to 6 carbon atoms (e.g., benzyl, phenethyl and 3-phenylpropyl), a heterocyclic group having 3 to 12 carbon atoms (e.g., pyridyl, pyrrolidinyl, piperidinyl, furl, and thienyl), or a heterocyclic-alkyl group comprising a heterocyclic group having 3 to 12 carbon atoms and an alkyl group having 1 to 6 carbon atoms (e.g., 3-indolylmethyl and 2-pyridyl-methyl).
R3 is a hydrogen atom, an alkyl group having 1 to 10 carbon atoms (preferably an alkyl group having 1 to 6 carbon atoms, optionally a linear, branched, or cyclic alkyl group, e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, pentyl, isopentyl and hexyl), an alkenyl group having 2 to 10 carbon atoms (preferably an alkenyl group having 2 to 6 carbon atoms, optionally a linear, a branched, or a cyclic alkenyl group, e.g., vinyl, 2-methyl-1-propenyl, and 2-cyclohexenyl), an alkynyl group having 2 to 10 carbon atoms (preferably an alkynyl group having 2 to 6 carbon atoms, optionally a linear or branched alkynyl group, e.g., 2-propynyl and 3-butynyl), an aryl group having 6 to 20 carbon atoms (e.g., phenyl and naphthyl), an aralkyl group comprising an aryl group having 6 to 20 carbon atoms and an alkyl group having 1 to 6 carbon atoms (e.g., benzyl, phenethyl and 3-phenylpropyl), a heterocyclic group having 3 to 12 carbon atoms (e.g., pyridyl, pyrrolidinyl, piperidinyl, furyl, and thienyl), or a heterocyclic-alkyl group comprising a heterocyclic group having 3 to 12 carbon atoms and an alkyl group having 1 to 6 carbon atoms (e.g., 3-indolylmethyl and 2-pyridylmethyl).
X is xe2x80x94Oxe2x80x94 or xe2x80x94NR4xe2x80x94 (in which R4 is a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, an aryl group having 6 to 20 carbon atoms, an aralkyl group comprising an aryl group having 6 to 20 carbon atoms and an alkyl group having 1 to 6 carbon atoms, a heterocyclic group having 3 to 12 carbon atoms, or a heterocyclic-alkyl group comprising a heterocyclic group having 3 to 12 carbon atoms and an alkyl group having 1 to 6 carbon atoms). Preferred carbon atom numbers for these alkyl, aryl, aralkyl and heterocyclic-alkyl groups and their concrete examples are those described above for R1, R2 and R3.
Y1 is OR5 (in which R5 is a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, an aryl group having 6 to 20 carbon atoms, an-aralkyl group comprising an aryl group having 6 to 20 carbon atoms and an alkyl group having 1 to 6 carbon atoms, an acyl group having 2 to 20 carbon atoms, a heterocyclic group having 3 to 12 carbon atoms, or a heterocyclic-alkyl group comprising a heterocyclic group having 3 to 12 carbon atoms and an alkyl group having 1 to 6 carbon atoms), SR6 (in which R4 is a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, an aryl group having 6 to 20 carbon atoms, an aralkyl group comprising an aryl group having 6 to 20 carbon atoms and an alkyl group having 1 to 6 carbon atoms, an acyl group having 2 to 20 carbon atoms, a heterocyclic group having 3 to 12 carbon atoms, or a heterocyclic-alkyl group comprising a heterocyclic group having 3 to 12 carbon atoms and an alkyl group having 1 to 6 carbon atoms), or NR7R8 (in which R7 is a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, an aryl group having 6 to 20 carbon atoms, an aralkyl group comprising an aryl group having 6 to 20 carbon atoms and an alkyl group having 1 to 6 carbon atoms, an acyl group having 2 to 20 carbon atoms, a heterocyclic group having 3 to 12 carbon atoms, a heterocyclic-alkyl group comprising a heterocyclic group having 3 to 12 carbon atoms and an alkyl group having 1 to 6 carbon atoms, and R8 is a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, an aryl group having 6 to 20 carbon atoms, an aralkyl group comprising an aryl group having 6 to 20 carbon atoms and an alkyl group having 1 to 6 carbon atoms, a heterocyclic group having 3 to 12 carbon atoms, or a heterocyclic-alkyl group comprising a heterocyclic group having 3 to 12 carbon atoms and an alkyl group having 1 to 6 carbon atoms) Preferred carbon atom numbers for these alkyl, aryl, aralkyl and heterocyclic-alkyl groups and their concrete examples are those described above for R1, R2 and R3.
Y2 is a hydrogen atom or an alkyl group having 1 to 10 carbon atoms (preferably an alkyl group having 1 to 6 carbon atoms, optionally a linear, branched, or cyclic alkyl group, e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, pentyl, isopentyl and hexyl).
In the formula (1), Y1 and Y2 can form alternatively, in combination with each other, xe2x95x90O, xe2x95x90S, xe2x95x90Nxe2x80x94R9 (in which R9 is a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, an aryl group having 6 to 20 carbon atoms, an aralkyl group comprising an aryl group having 6 to 20 carbon atoms and an alkyl group having 1 to 6 carbon atoms, a heterocyclic group having 3 to 12 carbon atoms, or a heterocyclic-alkyl group comprising a heterocyclic group having 3 to 12 carbon atoms and an alkyl group having 1 to 6 carbon atoms), or xe2x95x90Nxe2x80x94OR10 (in which R10 is a hydrogen atom, an alkyl group having 1 to 10 carbon atoms an aryl group having 6 to 20 carbon atoms, an aralkyl group comprising an aryl group having 6 to 20 carbon atoms and an alkyl group having 1 to 6 carbon atoms, a heterocyclic group having 3 to 12 carbon atoms, or a heterocyclic-alkyl group comprising a heterocyclic group having 3 to 12 carbon atoms and an alkyl group having 1 to 6 carbon atoms). Preferred carbon atom namers for these alkyl, aryl, aralkyl and heterocylic-alkyl groups and their concrete examples are those described above for R1, R2 and R3.
Particularly preferred epoxysuccinamide derivatives of the formula (1) and their physiologically acceptable salts are the following two cases.
1) an epoxysuccinamide derivative or its physiologically acceptable salt in which R2 is isobutyl or isopropyl, R3 is a hydrogen atom, Y1 is OR5 (R5 has the meaning defined above), and Y2 is a hydrogen atom Preferred carbon atom namers for the alkyl, aryl, aralkyl and hetero-cyclic-alkyl groups in the groups of R5 and their concrete examples are those described above for R1, R2, and R3.
2) an epoxysuccinamide derivative or its physiologically acceptable salt in which R2 is isobutyl or isopropyl, R3 is an aryl group having 6 to 20 carbon atoms, Y1 is OR5 (R5 has the meaning defined above), and Y2 is a hydrogen atom. Preferred carbon atom numbers for the alkyl, aryl, aralkyl and heterocyclic-alkyl groups in the groups of R5 and their concrete examples are those stated above fox R1, R2, and R3.
In the groups of Y1 and Y2 of the formula (1), each of the alkyl groups for R5 to R10 can have one or more substituents selected from the group consisting of hydroxyl, amino, alkylamino having 1-6 carbon atoms (e.g., methylamino, ethylamino, n-propylamino, and isobutyl-amino), dialkylaminio having 2-12 carbon atoms in total (e.g-, dimethylamino, methylethylamino and diethylamino), alkoxy having 1-6 carbon atoms (e.g., method, ethoxy, n-propoxy, isopropox, and n-butoxy), carboxyl, alkoxycarbonyl having 2-7 carbon atoms (e.g., ethoxyarbonyl), carbamoyl, alkylaminocarbonyl having 2-7 carbon atoms (e.g, methylaminocarbonyl and ethylaminocarbonyl), dialkylaminocarbonyl having 3-13 carbon atoms in total (e.g, dimethylaminocarbonyl, diethylaminocarbonyl, methylethylaminocarbonyl and piperadinocarbonyl), and guanidino.
Each of the aryl groups and the heterocyclic groups for R1 to R10 may have one or more substituents selected from the group consisting of alkyl having 1-6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, and n-butyl), hydroxyl, amino, alkylamino having 1-6 carbon atoms (e.g-, methylamino, ethylamino, and n-propylamino), dialkylamino having 2-12 carbon atoms in total (e.g., dimethylamino, methylethylamino and diethylamino), alkoxy having 1-6 carbon atoms (e.g., methoxy, ethoxy, n-propoxy and isopropoxy), halogen (e.g., fluorine, chlorine, and bromine), haloalkyl having 1-6 carbon atoms (e.g., trifluoromethyl), cyano, nitro, carboxyl, alkoxycarbonyl having 2-7 carbon atoms (e.g., ethoxycarbonyl), carbamoyl, alkylaminocarbonyl having 2-7 carbon atoms (e.g., methylaminocarbonyl and ethylaminocarbonyl), dialkyl-aminocarbonyl having 3-13 carbon atoms in total (eg., dimethylaminocarbonyl and methylethylaminocarbonyl), amidino, and quanidino.
The two carbon atoms of the oxirane ring of the aforementioned formula (1) both are asymmetric carbon atoms. The formula (1) means that the two carbonyl groups attached to the oxirane ring are in the trans conformation. Therefore, the epoxysuccinamide derivative of the invention can be either an optical isomer in the form of (T1) or (T2) mentioned below, or a mixture thereof 
Examples of the epoxysuccinamnide derivatives of the invention are set forth in the following Table 1 (Tables 1-1, 1-2, 1-3, and 1-4), wherein R1, R2, R3, X, Y1 and Y2 mean those shown in the aforementioned formula (1). In the following Table 1, each symbol means the following:
H: hydrogen, Me, methyl, Et: ethyl, Ph: phenyl, Bn: benzyl, iPr: isopropyl, iBu: isobutyl, sBu: sec-butyl, tBu: tert-butyl, cHex: cyclohexyl, 4-MePh: 4-methyl-phenyl, 4-ClPh: 4-chlorophenyl, 4-tBuPh: 4-tert-butyl-phenyl, 4xe2x80x2-HOBn: 4xe2x80x2-hydrobenzyl.
The epoxysuccinamide derivative of the invention can be employed in the form of a physiologically acceptable salt. For example, in the case that R1 is a hydrogen atom and X is xe2x80x94Oxe2x80x94, it forms a salt with an alkali metal (e.g., sodium or potassium), an alkaline earth metal (e.g., calcium), or an organic amine (e.g., triethylamine or pyridine).
Processes for preparing epoxysuccinamide derivatives of the invention are described below.
The epoxysuccinamide derivative of the intention can be prepared from the known compound by a process involving production of amide-bonding, esterification, or hydrolysis.
The respective reaction schemes are illustrated below.
1) Production of amide-bonding 
2) Production of amide-bonding (case of X=xe2x80x94NR4xe2x80x94) 
3) Esterification (case of R5 is alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, heterocyclic-carbonyl, or heterocyclic-alkylcarbonyl) 
4) Esterification (case of X=xe2x80x94Oxe2x80x94 and R1xe2x89xa0hydrogen) 
(in the above-illustrated reaction scheme, R0 is the same as R1 except that hydrogen is not included)
5) Hydrolysis (case of X=xe2x80x94Oxe2x80x94 and R1=hydrogen) 
(in the above-illustrated reaction scheme, R0 is the same as R1 except that hydrogen is not included)
In performing the above-illustrated reactions, groups such as R1 and/or Y1 can be protected by a known protective group, if necessary.
In the preparation of an epoxysuccinamide derivative of the invention, processes for preparing epoxysuccinamide derivatives described in Japanese Patent Publication No. 61-55509, Japanese Patent Provisional Publication No. 52-31024, H8-41043, H8-104684 and WO 96/30354 can be utilized. As for the detailed reaction conditions for preparing epoxysuccinamide derivatives of the invention, representative reaction conditions are stated in a great number of the working examples.
The epoxysuccinamide derivative of the invention can be administered by either oral or parenteral route. The oral formulation can be prepared in the form of tablets, capsules, powder, granules, or syrup. The parenteral administration can be performed through mucosal membrane, body surface, blood vessel, or tissue. The mucosal administration can be performed using ophthalmic solutions, inhalant, spray, or suppository. The surface administration can be performed using ointment. The administration through blood vessel and tissue can be performed using injections.
The oral formulation can be prepared using conventional excipient, disintegrator, binder, lubricant, dye and diluent. The excipient generally is glucose or lactose. The disintegrator can be starch or carboxymethyl cellulose calcium. The lubricant can be magnesium stearate or talc. The binder can be hydroxypropyl cellulose, gelatin, or polyvinyl alcohol.
The pharmaceutical composition for parenteral administration can be prepared in the conventional way. For instance, the injection can be prepared using an ordinary distilled water for injection, saline, or Ringer""s solution.
The dosage of the epoxysuccinamide derivative of the invention is in the range of 0.01 mg to 100 mg/day for adult in the case of using injection. In the case of oral administration, the dosage is in the range of 0.1 to 1 g/day for adult. The dosage can be increased or decreased depending on age, race, and conditions of patients.
[Industrial Utility]
The epoxysuccinamide derivative of the invention is a compound having inhibitory activities against cysteine proteases. The cysteine proteases encompass cathepsin L, cathepsin B, cathepsin K, calpain, etc. Therefore, an epoxysuccinamide derivative of the invention and its physiologically acceptable salt are expected to show pharmacological effects on diseases in which these proteases participate.
In more detail, examples of diseases in which cathepsin L and cathepsin K participate include bone diseases such as osteoporosis, malignant hypercalcemia, and Paget""s disease. Therefore, the epoxysuccinamide derivative of the invention and its physiologically acceptable salt are useful as pharmaceuticals for preventing or treating these bone diseases.
It is reported that cathepsin L and cathepsin B participate in joint destruction in arthritis and that an inhibitor against these cathepsins are effective in supressing the joint destruction in a rat arthritis model (Arthritis Rheum., 37, 236 (1994)), Further, it is reported that a cathepsin K inhibitor shows a similar effect in the rat arthritis model (J. Bone Miner Res., 11, 246 (1996).
Therefore, the epoxysuccinamide derivative of the invention and its physiologically acceptable salt are useful in treating osteoarthritis and rheumatoid arthritis.
The epoxysuccinamide derivative of the invention is also effective as a cathepsin B inhibitor,
In more detail, examples of diseases in which a cysteine protease such as cathepsin B participates include muscular dystrophy and muscular atrophy (in which cathepsin B and calpain participate), Alzheimer""s disease (in which calpain participates), and diseases which are considered to be caused by demyelination of neurocyte, such as multiple sclerosis and neuropathy of peripheral nervous system (in which calpain participates), cataract (in which calpain participates), allergic disorder (in which thiol protease participates), fulminant hepatitis (in which calpain participates), breast cancer, prostatic cancer, and prostatomegaly (in which calpain participates), hyperplasia and metastasis of cancer (in which cathepsin B and calpain participate), aggregation of platelet (in which calpain participates) (see Japanese Patent Provisional Publication No. H6-239835). Therefore, the epoxysuccinamide derivative of the invention is useful for treating and preventing these diseases.
The epoxysuccinamide derivative of the invention and its physiologically acceptable salt are expected to be useful for preventing and treating the above-mentioned diseases. Particularly, it is useful for prevention and treatment of bone diseases such as osteoporosis, malignant hypercalcemia and Paget""s disease, and of arthritis such as osteoarthritis and rheumatoid arthritis.